By 2050 older people at risk for cognitive decline and Alzheimer's (AD) are predicted to reach 13 million and health care costs are borne by individuals, their families, and society at large. Cholinergic dysfunction Is a main stay of AD and cholinesterase Inhibitor drug remain the mainstay for the management of mild to moderate AD. Our goal is to elucidate the earliest molecular and cellular events underlying the selective neuronal vulnerability ofthe cholinergic basal forebrain (CBF) memory connectome during the preclinical stage ofthe disease. Accomplishing this goal will be crucial for the development of novel disease modifying therapeutics for AD. In AD, the magnitude of cholinergic neuron and volume loss within the CBF subfields displays a rostrocaudal variation with the greatest cells loss in Its caudal subfield, which projects mainly to medial temporal cortex followed by its intermediate subfield, which projects to the lateral parietal lobule, and then to the rostral subfield, the least affected region, which innervates the frontal cortex. This suggests a circuit-based spatiotemporal course of CBF degeneration, which occurs in a caudal to rostral progression. CBF degeneration is not only manifested by specific post-translational modifications related to tau, but by a confluence of intracellular events related to endosomal-lysosomal (E-L) dysfunction and aberrant epigenetic events begin during preclinical AD. Data from the current grant revealed that select E-L gene products are upregulated in anterior cholinergic neurons along with their respective protein levels in MCI. We now report that neuronal E-L dysregulatlon progresses from the caudal to the rostral cholinergic subfields In MCI and In preclinical AD NCI. Accumulating data also implicate epigenetic factors in regulating lysosomal gene transcription and function In AD yet whether epigenetic changes effect E-L expression early in the disease remains unknown. We will apply site-specific tau, E-L and epigenetic antibodies and single cell array technology to the CBF subfields from preclinical AD and MCI cases. The subproject is well positioned to lay the groundwork for a wide range of potential Interventions that are truly distinct from approaches currently under investigation and may suggest novel biomarkers for the early diagnosis of dementia.